The present invention relates to a material which, when placed in contact with a tooth or other human or animal organomineral tissue, leads to remineralization of said tissue (dentin in the case of the tooth) The invention is especially useful for combating caries and other dental problems.
It is known that the development of caries can be partially restricted or inhibited by increasing the concentration of certain ions, especially fluoride, phosphate, calcium or, to a lesser extent, zinc ions. That is why some of these components are added in the form of water-soluble salts to drinking water, tooth pastes, elixirs for mouth rinses, etc. The positive effects of these salts are generally associated with their abrasive action or with their anti-microbial action.
The combined utilisation of said salts frequently gives rise to problems of incompatibility, such as the precipitation of insoluble products (e.g. calcium fluoride). In order to resolve the problem of chemical incompatibility, U.S. Pat. No. 3,978,206 (equivalent to DE 1.818.044) proposed the administration of ions by means of their release using carrier resins. But that patent considered solely the utilisation of resins carrying one type of ions: fluoride, phosphate or calcium, separately. And although in principle the disclosure of that patent does not exclude several ions being used in combination, nothing is said about the desirability of using a specific relative proportion of the ions.
Since it is known that caries and other dental problems are due to a demineralization of the components of the dentin (dental tissue), one possible channel of treatment lies in achieving the opposite effect, that is, partial remineralization of said components, which can lead to regeneration of the said dentin. But no suitable method is yet known in the art for obtaining this remineralization effect.
Furthermore, the current treatment of so-called deep caries (caries in which the bottom of the cavity reaches down very close to the upper end of the pulp containing the nerve) presents serious problems. One is associated with the fact that the material used for filling the cavity is mainly calcium hydroxide, which produces a strong alkaline reaction which can even intensify the pain. Moreover, the lactic acid produced by the bacteria continues to act and can even react by dissolving a significant amount of the filler or of the rest of the dentin. Finally, the usual fillers can give rise to thermal sensations (differences between cold and heat) or electrochemical sensations (due, for example, to acids or sugars), down to near the nerve, thereby causing discomfort. In any case, one of the greatest problems of deep caries is the possibility of bacterial infection of the pulp (pulpitis), which is very complicated to treat.
The present invention provides a satisfactory solution to these problems by means of controlled release of the Ca2+, Fxe2x88x92 and PO43xe2x88x92 ions on the basis of a mixture of ion-exchange resins, and in molar ratio close to that of the organomineral tissue to be remineralized. In the case of the teeth, the approximate ratio is that of fluoroapatite (Ca2FPO4), which is practically the same as in dentin. Control of release is implemented by mixing of slow-release resins (the ones of weak acid and weak base type) and fast-release resins (ones of strong acid and strong base type). Placed in contact with this mixture of resins, which is generally triturated in the form of mixture of granules (mixed beds), the organomineral tissues are remineralized in a surprisingly fast and effective way, especially if they are in the presence of Zn2+ ions.
Thus, one of the objects of the present invention is an organomineral tissue remineralizing material which, together with other accessory components and a sufficient quantity of water, physiological serum or artificial saliva to lend it the desired texture or pastiness, comprises a mixture of ion-exchange resins, cationic and anionic, charged with the cations and anions corresponding to the salts making up the organomineral tissue to be remineralized; These ions are in a molar ratio close to that corresponding to said tissue.
A preferred embodiment of the present invention is one in which the organomineral tissue to be regenerated is the dentin of human or animal teeth, in which the corresponding cations and anions are Ca2+, Fxe2x88x92 and PO43xe2x88x92, and the approximate molar ratio between them is 2:1:1, respectively. Particularly preferred is a material in which the resins also have a charge of ZN2+ ions representing a proportion lower than 1%, preferably close to 0.2%, of the dry weight of the resin. The zinc has a dual effect: on the one hand it is bactericidal, thereby helping to combat the micro-organisms which cause caries, and on the other hand it acts as an initiator or catalyst suitable for stimulating ionic release of the other structural ions.
Ion-exchange resins of any type known in the art can be used, such as the acrylic resins, though the ones preferred are those whose base is cross-linked polystyrene with 2-14% divinylbenzene.
It is advisable for the mixture of resins to include both cationic resins of weak acid character (functionalized with carboxylic acid groups and resins of strong acid character (functionalized with sulphonic acid groups). Similarly, it is also advisable for the mixture of resins to include both anionic resins of weak base character (functionalized with protonated tertiary amino groups) and anionic resins of strong base character (functionalized with quaternary ammonium groups).
The most suitable way of charging the Ca2+, Fxe2x88x92 and PO43xe2x88x92 ions in the resins is by in-column treatment of resins in their NaCl form, with aqueous solutions of CaCl2, NaF and Na3PO4, respectively. To charge the Zn2+ ion, it is advisable to use an aqueous solution of ZnCl.
A further object of the present invention is to provide a procedure for preparing organomineral tissue remineralizing material, characterized by succession of the following stages:
i) The desired quantities of suitably functionalized commercially available ion-exchange resins (anionic or cationic) are placed in columns;
ii) The resins are purified by washings with water and with a suitable organic solvent, preferably ethanol;
iii) The acid or base forms (H+ or OHxe2x88x92) of the resins are converted into the corresponding Na+ or Clxe2x88x92 forms, respectively, by treatments with NaCl (aq);
iv) The resins obtained in (iii) are treated with aqueous solutions of the corresponding salts: CaCl2 for introducing Ca2+ ions, Na3PO4 for introducing PO43xe2x88x92 ions, ZnCl for introducing Zn2+ ions, and NaF for introducing Fxe2x88x92 ions;
v) Excessive amounts of electrolyte are removed by washings with water;
vi) The resins are extracted from the columns, dried to ambient humidity conditions, and then pulverized; and
vii) The different resins are mixed to obtain the desired relative charges of the various ions.
Particularly preferred is the material described in Example 1 and the utilisation methodology described in Example 2. As illustrated in Example 2, the material object of the present invention is useful for preparing a composition for the treatment of teeth with caries, particularly with deep caries. Compared with the conventional material based on calcium hydroxide which is used for the first coating of the bottom of the cavity associated with caries, the material of the present invention has the advantage of not producing overcalcification, that is, of not producing a mineral deposit with a Ca/P ratio significantly higher than the value for a normal tooth. This overcalcification has been found to be associated with a passive mineralization which involves regressive changes in the pulp, e.g. sclerosis. Moreover, as is illustrated in Example 3, the microhardness of the bottom of the cavity following treatment with the material of the present invention is greater than following the conventional treatment of deep caries, which means an additional advantage.
The advantages of the material of the present invention show themselves above all in the treatment of deep caries, in which the nature of the first coating put in place is essential. An unsatisfactory first coating means that, even if the cavity is well covered by a secondary coating (phosphate cement) or a tertiary coating (silica, metals), the thermal or electrochemical changes which cause pain still reach down close to the nerve.
The advantages of the material of the present invention can be summarized thus: it produces practically complete remineralization of the dentin within a period of 3 to 5 weeks; it produces a prolonged action in the treatment leading to the formation of a film of calcium fluorophosphate on the interior surface of the cavity, of similar microhardness and morphology to those of the original dentin; it prevents painful reactions to cold/heat and to irritating substances such as acids or sweets; it more than doubles the speed of restoration of the functional capacity of the pulp; it prevents sclerosis of the gums by eliminating excessive calcinization of the predentin material; and it prevents penetration of microflora through the bottom of the caries cavity.
The material object of the present invention can be used for the preparation of any type of dentifrice products or products for improving dental health, such as pastes, elixirs, chewing gum or dental floss. Owing to its effect against caries and its remineralization effect in the zone of the tooth in contact with the gums, the material is also beneficial in the preventive or symptomatic treatment of other related mouth infections such as gingivitis.
The material can also be used in the preparation of a composition for the treatment of damaged bones, as in the case of fractured, demineralized or aged bones. In such cases the ionic charge of the resin mixture will have to be adjusted to the composition of the bones.
The examples, which follow, illustrate the present invention in a non-restrictive way.